Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1982 Oct;79(19):6038–6041. doi: 10.1073/pnas.79.19.6038

Glanzmann thrombasthenia: deficient binding of von Willebrand factor to thrombin-stimulated platelets.

Z M Ruggeri, R Bader, L de Marco
PMCID: PMC347047  PMID: 6310559

Abstract

Glanzmann thrombasthenia is an inherited bleeding disorder characterized by the failure of platelets to aggregate in response to almost all stimuli. However, thrombasthenic platelets will aggregate with bovine and porcine von Willebrand factor (vWF) and will show normal ristocetin-induced binding and aggregation in the presence of human vWF. In contrast, we now report that the specific binding of vWF to the thrombin-stimulated platelets was less than 20% of normal in three patients with Glanzmann thrombasthenia. Analysis of binding isotherms was based on the assumption of one class of binding sites for vWF on the platelet membrane. Double-reciprocal plots were used to calculate maximal binding at saturation and apparent dissociation constant (Kd). In nine normals, 2.82 +/- 0.64 micrograms (+/- SD) of vWF bound to 10(8) platelets at saturation, with Kd (+/- SD) = 3.65 +/- 1.23 micrograms/ml. In two patients with thrombasthenia binding was markedly decreased and did not approach saturation. In the third patient, binding at saturation corresponded to 0.21 micrograms per 10(8) platelets, with Kd = 3.93 micrograms/ml. These findings suggest that mechanisms underlying the vWF-platelet interaction are incompletely reflected in ristocetin-dependent assay systems. Moreover, these results, in addition to those previously reported for fibronectin, suggest that the platelet defect in Glanzmann thrombasthenia is not limited to decreased binding of fibrinogen but involves several glycoproteins that are known to interact with platelets.

Full text

PDF
6039

Images in this article

6040Image
on p.6040

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bennett J. S., Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest. 1979 Nov;64(5):1393–1401. doi: 10.1172/JCI109597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Clemetson K. J., Capitanio A., Pareti F. I., McGregor J. L., Lüscher E. F. Additional platelet membrane glycoprotein abnormalities in Glanzmann's thrombasthenia: A comparison with normals by high resolution two-dimensional polyacrylamide gel electrophoresis. Thromb Res. 1980 Jun 15;18(6):797–806. doi: 10.1016/0049-3848(80)90202-9. [DOI] [PubMed] [Google Scholar]
  3. De Marco L., Shapiro S. S. Properties of human asialo-factor VIII. A ristocetin-independent platelet-aggregating agent. J Clin Invest. 1981 Aug;68(2):321–328. doi: 10.1172/JCI110259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Fraker P. J., Speck J. C., Jr Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphrenylglycoluril. Biochem Biophys Res Commun. 1978 Feb 28;80(4):849–857. doi: 10.1016/0006-291x(78)91322-0. [DOI] [PubMed] [Google Scholar]
  5. Fujimoto T., Ohara S., Hawiger J. Thrombin-induced exposure and prostacyclin inhibition of the receptor for factor VIII/von Willebrand factor on human platelets. J Clin Invest. 1982 Jun;69(6):1212–1222. doi: 10.1172/JCI110560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gerrard J. M., Schollmeyer J. V., Phillips D. R., White J. G. alpha-Actinin deficiency in thrombasthenia: possible identity of alpha-actinin and glycoprotein III. Am J Pathol. 1979 Mar;94(3):509–528. [PMC free article] [PubMed] [Google Scholar]
  7. Girolami A., De Marco L., Virgolini L., Peruffo R., Fabris F. Platelet adhesiveness and aggregation in congenital afibrinogenemia. An investigation of three patients with post-transfusion, cross-correction studies between two of them. Blut. 1975 Feb;30(2):87–100. doi: 10.1007/BF01633963. [DOI] [PubMed] [Google Scholar]
  8. Hawiger J., Parkinson S., Timmons S. Prostacyclin inhibits mobilisation of fibrinogen-binding sites on human ADP- and thrombin-treated platelets. Nature. 1980 Jan 10;283(5743):195–197. doi: 10.1038/283195a0. [DOI] [PubMed] [Google Scholar]
  9. Jenkins C. S., Phillips D. R., Clemetson K. J., Meyer D., Larrieu M. J., Lüscher E. F. Platelet membrane glycoproteins implicated in ristocetin-induced aggregation. Studies of the proteins on platelets from patients with Bernard-Soulier syndrome and von Willebrand's disease. J Clin Invest. 1976 Jan;57(1):112–124. doi: 10.1172/JCI108251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kao K. J., Pizzo S. V., McKee P. A. Demonstration and characterization of specific binding sites for factor VIII/von Willebrand factor on human platelets. J Clin Invest. 1979 Apr;63(4):656–664. doi: 10.1172/JCI109348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kao K. J., Pizzo S. V., McKee P. A. Platelet receptors for human Factor VIII/von Willebrand protein: functional correlation of receptor occupancy and ristocetin-induced platelet aggregation. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5317–5320. doi: 10.1073/pnas.76.10.5317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kornecki E., Niewiarowski S., Morinelli T. A., Kloczewiak M. Effects of chymotrypsin and adenosine diphosphate on the exposure of fibrinogen receptors on normal human and Glanzmann's thrombasthenic platelets. J Biol Chem. 1981 Jun 10;256(11):5696–5701. [PubMed] [Google Scholar]
  13. Kunicki T. J., Aster R. H. Deletion of the platelet-specific alloantigen PlA1 from platelets in Glanzmann's thrombasthenia. J Clin Invest. 1978 May;61(5):1225–1231. doi: 10.1172/JCI109038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moake J. L., Olson J. D., Troll J. H., Tang S. S., Funicella T., Peterson D. M. Binding of radioiodinated human von Willebrand factor to Bernard-Soulier, thrombasthenic and von Willebrand's disease platelets. Thromb Res. 1980 Jul 1;19(1-2):21–27. doi: 10.1016/0049-3848(80)90400-4. [DOI] [PubMed] [Google Scholar]
  15. Mustard J. F., Kinlough-Rathbone R. L., Packham M. A., Perry D. W., Harfenist E. J., Pai K. R. Comparison of fibrinogen association with normal and thrombasthenic platelets on exposure to ADP or chymotrypsin. Blood. 1979 Nov;54(5):987–993. [PubMed] [Google Scholar]
  16. Nachman R. L., Leung L. L. Complex formation of platelet membrane glycoproteins IIb and IIIa with fibrinogen. J Clin Invest. 1982 Feb;69(2):263–269. doi: 10.1172/JCI110448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nurden A. T., Caen J. P. An abnormal platelet glycoprotein pattern in three cases of Glanzmann's thrombasthenia. Br J Haematol. 1974 Oct;28(2):253–260. doi: 10.1111/j.1365-2141.1974.tb06660.x. [DOI] [PubMed] [Google Scholar]
  18. Nurden A. T., Dupuis D., Kunicki T. J., Caen J. P. Analysis of the glycoprotein and protein composition of Bernard-Soulier platelets by single and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. J Clin Invest. 1981 May;67(5):1431–1440. doi: 10.1172/JCI110172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Peerschke E. I., Zucker M. B., Grant R. A., Egan J. J., Johnson M. M. Correlation between fibrinogen binding to human platelets and platelet aggregability. Blood. 1980 May;55(5):841–847. [PubMed] [Google Scholar]
  20. Phillips D. R., Agin P. P. Platelet membrane defects in Glanzmann's thrombasthenia. Evidence for decreased amounts of two major glycoproteins. J Clin Invest. 1977 Sep;60(3):535–545. doi: 10.1172/JCI108805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Plow E. F., Ginsberg M. H. Specific and saturable binding of plasma fibronectin to thrombin-stimulated human platelets. J Biol Chem. 1981 Sep 25;256(18):9477–9482. [PubMed] [Google Scholar]
  22. Plow E. F., Marguerie G. A. Participation of ADP in the binding of fibrinogen to thrombin-stimulated platelets. Blood. 1980 Sep;56(3):553–555. [PubMed] [Google Scholar]
  23. Ruggeri Z. M., Zimmerman T. S. The complex multimeric composition of factor VIII/von Willebrand factor. Blood. 1981 Jun;57(6):1140–1143. [PubMed] [Google Scholar]
  24. Tollefsen D. M., Majerus P. W. Inhibition of human platelet aggregation by monovalent antifibrinogen antibody fragments. J Clin Invest. 1975 Jun;55(6):1259–1268. doi: 10.1172/JCI108045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Walsh P. N., Mills D. C., White J. G. Metabolism and function of human platelets washed by albumin density gradient separation. Br J Haematol. 1977 Jun;36(2):287–296. doi: 10.1111/j.1365-2141.1977.tb00649.x. [DOI] [PubMed] [Google Scholar]
  26. Weiss H. J., Baumgartner H. R., Tschopp T. B., Turitto V. T., Cohen D. Correction by factor VIII of the impaired platelet adhesion to subendothelium in von Willebrand disease. Blood. 1978 Feb;51(2):267–279. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES